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1.
J Trop Pediatr ; 68(5)2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35962981

RESUMO

OBJECTIVES: Clinical data with respect to the impact of meconium on the prognosis of neonatal bacterial meningitis are scarce. Therefore, in this study, we aimed to determine whether meconium-stained amniotic fluid (MSAF) represents a risk factor for poor prognosis of neonatal bacterial meningitis in a confirmed case population. METHODS: This was a retrospective cohort study of 256 neonates diagnosed with bacterial meningitis hospitalized at one of three hospitals in Shantou, China, between October 2013 and September 2018. Clinical manifestation, laboratory test results and treatment were compared between the two groups, with outcomes dichotomized into 'good' or 'poor' prognosis. Multivariate analysis and follow-up logistic regression analysis were used to identify predictive factors of a poor outcome. RESULTS: Of the 256 neonates with BM, 95 (37.1%) had a good prognosis at discharge and 161 (62.9%) had a poor prognosis. In the poor prognosis group, 131/161 (79.4%) neonates had a permanent neurological sequelae and 19 (11.8%) had ≥2 sequelae. Of note, 11 neonates died. The rate of poor prognosis of BM was significantly higher among neonates with than without MSAF (26.1% vs. 12.6%, respectively; p < 0.05). A logistic multivariate analysis to evaluate the prognostic effect of MSAF to BM showed that neonatal with MSAF is more likely to have a worse prognosis of BM [unadjusted odds ratio (OR), 2.44, 95% confidence interval (CI), 1.24-5.10; adjusted OR, 2.31; 95% CI, 1.09-5.17]. CONCLUSION: MSAF is significantly associated with poor prognosis of neonatal bacterial meningitis. Therefore, in case of MSAF, more attention should be paid to neonatal bacterial meningitis.


Assuntos
Doenças do Recém-Nascido , Meningites Bacterianas , Complicações na Gravidez , Líquido Amniótico , Feminino , Humanos , Recém-Nascido , Mecônio , Meningites Bacterianas/diagnóstico , Estudos Retrospectivos
2.
Front Microbiol ; 13: 845173, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35547113

RESUMO

Antibiotic-resistant Pseudomonas aeruginosa is insensitive to antibiotics and difficult to deal with. An understanding of the resistance mechanisms is required for the control of the pathogen. In this study, gas chromatography-mass spectrometer (GC-MS)-based metabolomics was performed to identify differential metabolomes in ciprofloxacin (CIP)-resistant P. aeruginosa strains that originated from P. aeruginosa ATCC 27853 and had minimum inhibitory concentrations (MICs) that were 16-, 64-, and 128-fold (PA-R16CIP, PA-R64CIP, and PA-R128CIP, respectively) higher than the original value, compared to CIP-sensitive P. aeruginosa (PA-S). Upregulation of fatty acid biosynthesis forms a characteristic feature of the CIP-resistant metabolomes and fatty acid metabolome, which was supported by elevated gene expression and enzymatic activity in the metabolic pathway. The fatty acid synthase inhibitor triclosan potentiates CIP to kill PA-R128CIP and clinically multidrug-resistant P. aeruginosa strains. The potentiated killing was companied with reduced gene expression and enzymatic activity and the returned abundance of fatty acids in the metabolic pathway. Consistently, membrane permeability was reduced in the PA-R and clinically multidrug-resistant P. aeruginosa strains, which were reverted by triclosan. Triclosan also stimulated the uptake of CIP. These findings highlight the importance of the elevated biosynthesis of fatty acids in the CIP resistance of P. aeruginosa and provide a target pathway for combating CIP-resistant P. aeruginosa.

3.
Ital J Pediatr ; 47(1): 116, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039399

RESUMO

BACKGROUND: Capillary leak syndrome (CLS) is a rare disease characterized by profound vascular leakage and presents as a classic triad of hypotension, hypoalbuminemia and hemoconcentration. Severe CLS is mostly induced by sepsis and generally life-threatening in newborns, especially in premature infants. Continuous renal replacement therapy (CRRT) plays an important role of supportive treatment for severe CLS. Unfortunately, CRRT in preterm infants has rarely been well defined. CASE PRESENTATION: We report the case of a 11-day-old girl with CLS caused by sepsis, who was delivered by spontaneous vaginal delivery (SVD) at gestational age of 25 weeks and 4 days, and a birth weight of 0.89 Kilograms(kg). The infant received powerful management consisting of united antibiotics, mechanical ventilation, intravenous albumin and hydroxyethyl starch infusion, vasoactive agents, small doses of glucocorticoids and other supportive treatments. However, the condition rapidly worsened with systemic edema, hypotension, pulmonary exudation, hypoxemia and anuria in about 40 h. Finally, we made great efforts to perform CRRT for her. Fortunately, the condition improved after 82 h' CRRT, and the newborn was rescued and gradually recovered. CONCLUSION: CRRT is an effective rescue therapeutic option for severe CLS and can be successfully applied even in extremely-low-birth-weight premature.


Assuntos
Síndrome de Vazamento Capilar/terapia , Terapia de Substituição Renal Contínua , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido Prematuro , Síndrome de Vazamento Capilar/etiologia , Feminino , Humanos , Recém-Nascido , Sepse/complicações
4.
Stem Cells Int ; 2020: 5939530, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32399044

RESUMO

BACKGROUND: Shear stress is an effective modulator of endothelial progenitor cells (EPCs) and has been suggested to play an important role in angiogenesis. The phosphatase and tensin homolog (PTEN)/Akt and guanosine triphosphate cyclohydrolase (GTPCH)/tetrahydrobiopterin (BH4) pathways regulate the function of early EPCs. However, the role of these pathways in the shear stress-induced angiogenesis of late EPCs remains poorly understood. Therefore, we aim to investigate whether shear stress could upregulate the angiogenesis capacity of late EPCs and to further explore the possible underlying mechanisms. METHODS: Late EPCs were subjected to laminar shear stress (LSS), and their in vitro migration, proliferation, and tube formation capacity were determined. In addition, the in vivo angiogenesis capacity was explored, along with the expression of molecules involved in the PTEN/Akt and GTPCH/BH4 pathways. RESULTS: LSS elevated the in vitro activities of late EPCs, which were accompanied by downregulated PTEN expression, accelerated Akt phosphorylation, and GTPCH/BH4 pathway activation (all P < 0.05). Following Akt inhibition, LSS-induced upregulated GTPCH expression, BH4, and NO level of EPCs were suppressed. LSS significantly improved the migration, proliferation, and tube formation ability (15 dyn/cm2 LSS vs. stationary: 72.2 ± 5.5 vs. 47.3 ± 7.3, 0.517 ± 0.05 vs. 0.367 ± 0.038, and 1.664 ± 0.315 vs. 1 ± 0, respectively; all P < 0.05) along with the in vivo angiogenesis capacity of late EPCs, contributing to the recovery of limb ischemia. These effects were also blocked by Akt inhibition or GTPCH knockdown (P < 0.05, respectively). CONCLUSIONS: This study provides the first evidence that shear stress triggers angiogenesis in late EPCs via the PTEN/Akt/GTPCH/BH4 pathway, providing a potential nonpharmacologic therapeutic strategy for promoting angiogenesis in ischemia-related diseases.

5.
Cardiol Res Pract ; 2020: 7361434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411450

RESUMO

AIM: The slow coronary flow (SCF) phenomenon was characterized by delayed perfusion of epicardial arteries, and no obvious coronary artery lesion in coronary angiography. The prognosis of patients with slow coronary flow was poor. However, there is lack of rapid, simple, and accurate method for SCF diagnosis. This study aimed to explore the utility of plasma choline as a diagnostic biomarker for SCF. METHODS: Patients with coronary artery stenosis <40% evaluated by the coronary angiogram method were recruited in this study and were grouped into normal coronary flow (NCF) and SCF by thrombolysis in myocardial infarction frame count (TFC). Plasma choline concentrations of patients with NCF and SCF were quantified by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry. Correlation analysis was performed between plasma choline concentration and TFC. Receiver operating characteristic (ROC) curve analysis with or without confounding factor adjustment was applied to predict the diagnostic power of plasma choline in SCF. RESULTS: Forty-four patients with SCF and 21 patients with NCF were included in this study. TFC in LAD, LCX, and RCA and mean TFC were significantly higher in patients with SCF in comparison with patients with NCF (32.67 ± 8.37 vs. 20.66 ± 3.41, P < 0.01). Plasma choline level was obviously higher in patients with SCF when compared with patients with NCF (754.65 ± 238.18 vs. 635.79 ± 108.25, P=0.007). Plasma choline level had significantly positive correlation with Mean TFC (r = 0.364, P=0.002). Receiver operating characteristic (ROC) analysis showed that choline with or without confounding factor adjustment had an AUC score of 0.65 and 0.77, respectively. CONCLUSIONS: TFC were closely related with plasma choline level, and plasma choline can be a suitable and stable diagnostic biomarker for SCF.

6.
Vaccine ; 38(23): 3960-3967, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32321685

RESUMO

This study investigated the concentrations and seroprevalence of immunoglobulin G (IgG) antibodies against pertussis, diphtheria, tetanus, measles, mumps and rubella among children in Guangzhou, China. We conducted a cross-sectional study focusing on the post-vaccination immune statuses of children on scheduled immunisation. Human IgG antibody against six diseases were measured using commercial enzyme-linked immunosorbent assay kits. Of 620 subjects, the male-to-female ratio was 2.04 (416/204). Seroprevalence (81.97% vs 90.20%) and IgG concentrations (686.55 IU/mL vs 884.26 IU/mL, P < 0.05) for measles, tetanus (0.94 IU/mL vs 1.21 IU/mL) and rubella (34.33 IU/mL vs 47.37 IU/mL) were all higher in females. No differences based on sex were observed in the seroprevalence and IgG concentrations for anti-pertussis antibodies, anti-diphtheria antibodies and anti-mumps. Slight increase in seroprevalence and IgG concentration occurred with anti-pertussis antibodies after primary and booster vaccinations (from 0.00% [1 m], 5.45% [6 m], to 17.14% [1.5 yr]; and from 8.57% [5 yr] to 15.79% [6 yr]). Although no booster vaccination was given after age 6 yr, the seroprevalence and IgG concentration for anti-pertussis antibodies remained relatively stable. For diphtheria, tetanus, measles and rubella, seroprevalence reached their peaks after the primary and first booster vaccination. A plateau occurred after age 1.5 yr with a declining trend in subjects >8-10 yr. The IgG concentrations of these 4 pathogens showed a dramatic increase after primary vaccination, with steadily declining trends thereafter. For mumps, subjects showed increased seroprevalence and IgG concentration after the primary mumps-containing vaccination in 1.5-yr-olds (from 7.14% to 57.14%; 52.13 IU/mL to 214.18 IU/mL); however, following that low seroprevalence levels (from 42.86% to 80.00%) were observed. The post-vaccination immune statuses against diphtheria, tetanus, measles and rubella were relatively satisfactory, compared to those against pertussis and mumps. Booster vaccination against pertussis and mumps at appropriate time should be considered.


Assuntos
Difteria , Sarampo , Caxumba , Rubéola (Sarampo Alemão) , Tétano , Coqueluche , Humanos , Criança , Masculino , Feminino , Lactente , Estudos Transversais , Caxumba/epidemiologia , Caxumba/prevenção & controle , Estudos Soroepidemiológicos , Difteria/epidemiologia , Difteria/prevenção & controle , Tétano/prevenção & controle , Coqueluche/epidemiologia , Coqueluche/prevenção & controle , Anticorpos Antivirais , Rubéola (Sarampo Alemão)/epidemiologia , Rubéola (Sarampo Alemão)/prevenção & controle , Vacinação , Imunização Secundária , China/epidemiologia , Imunoglobulina G
7.
J Cell Mol Med ; 24(2): 2052-2063, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31883300

RESUMO

Studies have demonstrated that nuclear factor of activated T cells 5 (NFAT5) is not only a tonicity-responsive transcription factor but also activated by other stimuli, so we aim to investigate whether NFAT5 participates in collateral arteries formation in rats. We performed femoral artery ligature (FAL) in rats for hindlimb ischaemia model and found that NFAT5 was up-regulated in rat adductors with FAL compared with sham group. Knockdown of NFAT5 with locally injection of adenovirus-mediated NFAT5-shRNA in rats significantly inhibited hindlimb blood perfusion recovery and arteriogenesis. Moreover, NFAT5 knockdown decreased macrophages infiltration and monocyte chemotactic protein-1 (MCP-1) expression in rats adductors. In vitro, with interleukin-1ß (IL-1ß) stimulation and loss-of-function studies, we demonstrated that NFAT5 knockdown inhibits MCP-1 expression in endothelial cells and chemotaxis of THP-1 cells regulated by ERK1/2 pathway. More importantly, exogenous MCP-1 delivery could recover hindlimb blood perfusion, promote arteriogenesis and macrophages infiltration in rats after FAL, which were depressed by NFAT5 knockdown. Besides, NFAT5 knockdown also inhibited angiogenesis in gastrocnemius muscles in rats. Our results indicate that NFAT5 is a critical regulator of arteriogenesis and angiogenesis via MCP-1-dependent monocyte recruitment, suggesting that NFAT5 may represent an alternative therapeutic target for ischaemic diseases.


Assuntos
Artérias/embriologia , Artérias/metabolismo , Quimiocina CCL2/metabolismo , Monócitos/metabolismo , Organogênese , Fatores de Transcrição/metabolismo , Animais , Núcleo Celular/metabolismo , Quimiotaxia , Circulação Colateral , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Membro Posterior/irrigação sanguínea , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Interleucina-1beta/metabolismo , Isquemia/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Transporte Proteico , Ratos Sprague-Dawley , Células THP-1
8.
Epigenomics ; 11(2): 199-213, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30657346

RESUMO

AIM: The study aimed to investigate the role of circular RNA circASS1 in breast cancer cells. MATERIALS & METHODS: Circular RNAs microarray expression profile were analyzed in MCF-7, MDA-MB-231, and qRT-PCR and western blotting were used to quantify expression of circASS1 and its parental gene ASS1. Wound healing, migration and invasion assay were performed. Luciferase assay system was used to detect harbored miRNA. RESULTS: CircASS1 in MDA-MB-231 is downregulated comparing to MCF-7, and overexpression of circASS1 could suppress invasion and migration. While silence, it could promote invasion and migration. MiR-4443 functioning as a tumor promoter gene could be captured by circASS1. ASS1 is upregulated in loss-of-function experiments, while downregulated in gain-of-function experiments. CONCLUSION: CircASS1 suppresses invasion and migration capacity of breast cancer cells and harbored miR-4443.


Assuntos
Neoplasias da Mama/genética , MicroRNAs/genética , RNA Circular/genética , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo , Feminino , Humanos , Células MCF-7 , MicroRNAs/metabolismo , RNA Circular/metabolismo
9.
Epigenomics ; 10(11): 1499-1509, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30309258

RESUMO

Exosomes are small membrane vesicles with a diameter of 40-100 nm, which are released into the intracellular environment. Exosomes could influence the genetic and epigenetic changes of receptor cells by promoting the horizontal transfer of various proteins or RNAs, especially miRNAs. Moreover, exosomes also play an important role in tumor microenvironment. Exosomes could promote the short- and long-distance exchanges of genetic information by acting as mediators of cell-to-cell communication. In addition, exosomes participate in drug resistance of tumor cells by genetic exchange between cells. It is reported that exosomes could be absorbed by recipient cells and transmit chemoresistance from drug-resistant tumor cells to sensitive ones. Then understanding the mechanisms of chemotherapy failure and controlling tumor progression effectively will be a major challenge for us. Therefore, in this review, we will briefly reveal the role of exosomes in drug resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Exossomos/metabolismo , Neoplasias/metabolismo , Animais , Exossomos/genética , Humanos , MicroRNAs/genética , Neoplasias/genética
10.
Biomed Pharmacother ; 107: 1342-1353, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30257349

RESUMO

OBJECTIVES: Accumulating evidence has been reported that circular RNAs (circRNAs) are a class of relatively stable, non-coding RNAs, which are involved in the progression of many types of diseases. However, the mechanism of hsa_circ_0052112 in breast cancer cells is not entirely clear. Hsa_circ_0052112, generated from the ZNF83 gene, is selected by analyzing circRNA expression profiles of breast cancer cell by using microarray assay. In this study, we will show the role of hsa_circ_0052112 in regulating cell invasion and migration in breast cancer. METHODS: The expression level of hsa_circ_0052112 in MCF-7 and MDA-MB-231 cells was detected by RT-qPCR; we performed transwell assay to evaluate breast cancer cells' migration and invasion; predicated circRNA/miRNAs interaction using the miRanda and RNAhybrid software; identified the relationship between hsa_circ_0052112 and miR-125a-5p by luciferase activity assay and show the localization of hsa_circ_0052112 by FISH assay and show the significance of ZNF83 in clinical prognosis by Kaplan-Meier survival analysis. RESULTS: Hsa_circ_0052112 expression was significantly higher in MDA-MB-231 cells than that in MCF-7 cells. Overexpression of hsa_circ_0052112 promoted cell migration and invasion in breast cancer. Inversely, down-regulation of hsa_circ_0052112 suppressed breast cancer cells migration and invasion. Hsa_circ_0052112 was mostly located in cytoplasm. Hsa_circ_0052112 could directly sponge to miR-125a-5p; overexpression of miR-125a-5p significantly inhibited breast cancer cells migration and invasion. However, high or low expression of miR-125a-5p was not correlated with relapse free survival (RFS) by TCGA database validation, but high expression of ZNF83 was closely correlated with poor RFS by Kaplan-Meier plotter. CONCLUSIONS: These data suggest that hsa_circ_0052112 may be a potent biomarker for breast cancer, and may provide a new perspective on treatment of breast cancer.


Assuntos
Neoplasias da Mama/genética , Movimento Celular/genética , MicroRNAs/genética , RNA/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Células MCF-7 , Invasividade Neoplásica , RNA Circular , Regulação para Cima
11.
Epigenomics ; 10(9): 1229-1242, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30182731

RESUMO

AIM: To study the role of hsa_circ_0072995 in regulating the invasion and migration of breast cancer cells. MATERIALS & METHODS: Hsa_circ_0072995 expression was confirmed by quantitative real-time PCR; evaluating the migration and invasion of breast cancer cells through transwell assay; predicating circRNA/microRNAs interaction using the miRanda and RNAhybrid software; identifying the relationship between hsa_circ_0072995 and miR-30c-2-3p by luciferase activity assay; detecting the location of hsa_circ_0072995 by Fluorescence in situ hybridization assay. RESULTS: Hsa_circ_0072995 was significantly upregulated in MDA-MB-231 cells compared with MCF-7 cells. Hsa_circ_0072995 regulated the invasion and migration of breast cancer cells. Hsa_circ_0072995 existed in the nucleus and cytoplasm, and the proportion of the two was roughly equal. Hsa_circ_0072995 bound to miR-30c-2-3p. Overexpression of miR-30c-2-3p inhibited breast cancer cells migration and invasion. Low expression of miR-30c-2-3p was correlated with poor overall survival by The Cancer Genome Atlas database. CONCLUSION: Hsa_circ_0072995 may be a novel biomarker for breast cancer, and may function in metastasis of breast cancer.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Movimento Celular/genética , MicroRNAs/genética , RNA/genética , Linhagem Celular Tumoral , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Células MCF-7 , Invasividade Neoplásica , RNA Circular , Regulação para Cima
12.
Circulation ; 138(4): 397-411, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-29431644

RESUMO

BACKGROUND: Nitrates are widely used to treat coronary artery disease, but their therapeutic value is compromised by nitrate tolerance, because of the dysfunction of prostaglandin I2 synthase (PTGIS). MicroRNAs repress target gene expression and are recognized as important epigenetic regulators of endothelial function. The aim of this study was to determine whether nitrates induce nitrovasodilator resistance via microRNA-dependent repression of PTGIS gene expression. METHODS: Nitrovasodilator resistance was induced by nitroglycerin (100 mg·kg-1·d-1, 3 days) infusion in Apoe-/- mice. The responses of aortic arteries to nitric oxide donors were assessed in an organ chamber. The expression levels of microRNA-199 (miR-199)a/b were assayed by quantitative reverse transcription polymerase chain reaction or fluorescent in situ hybridization. RESULTS: In cultured human umbilical vein endothelial cells, nitric oxide donors induced miR-199a/b endogenous expression and downregulated PTGIS gene expression, both of which were reversed by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt or silence of serum response factor. Evidence from computational and luciferase reporter gene analyses indicates that the seed sequence of 976 to 982 in the 3'-untranslated region of PTGIS mRNA is a target of miR-199a/b. Gain functions of miR-199a/b resulting from chemical mimics or adenovirus-mediated overexpression increased PTGIS mRNA degradation in HEK293 cells and human umbilical vein endothelial cells. Furthermore, nitroglycerin-decreased PTGIS gene expression was prevented by miR-199a/b antagomirs or was mirrored by the enforced expression of miR-199a/b in human umbilical vein endothelial cells. In Apoe-/- mice, nitroglycerin induced the ectopic expression of miR-199a/b in the carotid arterial endothelium, decreased PTGIS gene expression, and instigated nitrovasodilator resistance, all of which were abrogated by miR-199a/b antagomirs or LNA-anti-miR-199. It is important that the effects of miR-199a/b inhibitions were abolished by adenovirus-mediated PTGIS deficiency. Moreover, the enforced expression of miR-199a/b in vivo repressed PTGIS gene expression and impaired the responses of aortic arteries to nitroglycerin/sodium nitroprusside/acetylcholine/cinaciguat/riociguat, whereas the exogenous expression of the PTGIS gene prevented nitrovasodilator resistance in Apoe-/- mice subjected to nitroglycerin infusion or miR-199a/b overexpression. Finally, indomethacin, iloprost, and SQ29548 improved vasorelaxation in nitroglycerin-infused Apoe-/- mice, whereas U51605 induced nitrovasodilator resistance. In humans, the increased expressions of miR-199a/b were closely associated with nitrate tolerance. CONCLUSIONS: Nitric oxide-induced ectopic expression of miR-199a/b in endothelial cells is required for nitrovasodilator resistance via the repression of PTGIS gene expression. Clinically, miR-199a/b is a novel target for the treatment of nitrate tolerance.


Assuntos
Aorta/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Resistência a Medicamentos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Oxirredutases Intramoleculares/metabolismo , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico/metabolismo , Nitroglicerina/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta/enzimologia , Sistema Enzimático do Citocromo P-450/genética , Resistência a Medicamentos/genética , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Oxirredutases Intramoleculares/genética , Masculino , Camundongos Knockout para ApoE , MicroRNAs/genética , MicroRNAs/metabolismo , Doadores de Óxido Nítrico/metabolismo , Nitroglicerina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima , Vasodilatadores/metabolismo
13.
Theranostics ; 8(22): 6163-6177, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30613290

RESUMO

Exosomes (Exo) secreted from hypoxia-conditioned bone marrow mesenchymal stem cells (BM-MSCs) were found to be protective for ischemic disease. However, the role of exosomal miRNA in the protective effect of hypoxia-conditioned BM-MSCs-derived Exo (Hypo-Exo) remains largely uncharacterized and the poor specificity of tissue targeting of Exo limits their clinical applications. Therefore, the objective of this study was to examine the effect of miRNA in Hypo-Exo on the repair of ischemic myocardium and its underlying mechanisms. We further developed modified Hypo-Exo with high specificity to the myocardium and evaluate its therapeutic effects. Methods: Murine BM-MSCs were subjected to hypoxia or normoxia culture and Exo were subsequently collected. Hypo-Exo or normoxia-conditioned BM-MSC-derived Exo (Nor-Exo) were administered to mice with permanent condition of myocardial infarction (MI). After 28 days, to evaluate the therapeutic effects of Hypo-Exo, infarction area and cardio output in Hypo-Exo and Nor-Exo treated MI mice were compared through Masson's trichrome staining and echocardiography respectively. We utilized the miRNA array to identify the significantly differentially expressed miRNAs between Nor-Exo and Hypo-Exo. One of the most enriched miRNA in Hypo-Exo was knockdown by applying antimiR in Hypoxia-conditioned BM-MSCs. Then we performed intramyocardial injection of candidate miRNA-knockdown-Hypo-Exo in a murine MI model, changes in the candidate miRNA's targets expression of cardiomyocytes and the cardiac function were characterized. We conjugated Hypo-Exo with an ischemic myocardium-targeted (IMT) peptide by bio-orthogonal chemistry, and tested its targeting specificity and therapeutic efficiency via systemic administration in the MI mice. Results: The miRNA array revealed significant enrichment of miR-125b-5p in Hypo-Exo compared with Nor-Exo. Administration of miR-125b knockdown Hypo-Exo significantly increased the infarction area and suppressed cardiomyocyte survival post-MI. Mechanistically, miR-125b knockdown Hypo-Exo lost the capability to suppress the expression of the proapoptotic genes p53 and BAK1 in cardiomyocytes. Intravenous administration of IMT-conjugated Hypo-Exo (IMT-Exo) showed specific targeting to the ischemic lesions in the injured heart and exerted a marked cardioprotective function post-MI. Conclusion: Our results illustrate a new mechanism by which Hypo-Exo-derived miR125b-5p facilitates ischemic cardiac repair by ameliorating cardiomyocyte apoptosis. Furthermore, our IMT- Exo may serve as a novel drug carrier that enhances the specificity of drug delivery for ischemic disease.


Assuntos
Apoptose , Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Oxigênio/metabolismo , Animais , Exossomos/genética , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo
14.
Biosci Rep ; 37(5)2017 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-28928231

RESUMO

Circular RNAs (circRNAs) are recently regarded as a naturally forming family of widespread and diverse endogenous noncoding RNAs (ncRNAs) that may regulate gene expression in mammals. At present, above 30000 circRNAs have already been found, with their unique structures to maintain stability more easily than linear RNAs. Several previous literatures stressed on the important role of circRNAs, whose expression was relatively correlated with patients' clinical characteristics and grade, in the carcinogenesis of cancer. CircRNAs are involved in many regulatory bioprocesses of malignance, including cell cycle, tumorigenesis, invasion, metastasis, apoptosis, vascularization, through adsorbing RNA as a sponge, binding to RNA-binding protein (RBP), modulating transcription, or influencing translation. Therefore, it is inevitable to further study the interactions between circRNAs and tumors and to develop novel circRNAs as molecular markers or potential targets, which will provide promising applications in early diagnosis, therapeutic evaluation, prognosis prediction of tumors and even gene therapy for tumors.


Assuntos
Carcinogênese/genética , Neoplasias/genética , Neovascularização Patológica/genética , RNA/genética , Apoptose/genética , Humanos , MicroRNAs/genética , Neoplasias/patologia , Neovascularização Patológica/patologia , RNA Circular , RNA não Traduzido/genética
15.
Arterioscler Thromb Vasc Biol ; 37(5): 957-968, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28254819

RESUMO

OBJECTIVE: To identify circulating microRNAs that are differentially expressed in severe coronary heart disease with well or poorly developed collateral arteries and to investigate their mechanisms of action in vivo and in vitro. APPROACH AND RESULTS: In our study, we identified a circulating microRNA, miR-15b-5p, with low expression that, nevertheless, characterized patients with sufficient coronary collateral artery function. Moreover, in murine hindlimb ischemia model, in situ hybridization identified that miR-15b-5p was specifically expressed in vascular endothelial cells of adductors in sham group and was remarkably downregulated after femoral artery ligation. Overexpressed miR-15b-5p significantly inhibited arteriogenesis and angiogenesis in mice. In vitro, both under basal and vascular endothelial growth factor stimulation, loss-of-function or gain-of-function studies suggested that miR-15b-5p significantly promoted or depressed the migration and proliferation of endothelial cells. We identified AKT3 (protein kinase B-3) as a direct target of miR-15b-5p. Interestingly, AKT3 deficiency by injection with Chol-AKT3-siRNA obviously suppressed arteriogenesis and the recovery of blood perfusion after femoral ligation in mice. CONCLUSIONS: These results indicate that circulating miR-15b-5p is a suitable biomarker for discriminating between patients with well-developed or poorly developed collaterals. Moreover, miR-15b-5p is a key regulator of arteriogenesis and angiogenesis, which may represent a potential therapeutic target for ischemic disease.


Assuntos
Circulação Colateral , Doença da Artéria Coronariana/enzimologia , Circulação Coronária , Vasos Coronários/enzimologia , Isquemia/enzimologia , MicroRNAs/metabolismo , Músculo Esquelético/irrigação sanguínea , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Membro Posterior , Humanos , Isquemia/genética , Isquemia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Neovascularização Fisiológica , Proteínas Proto-Oncogênicas c-akt/genética , Interferência de RNA , Transdução de Sinais , Transfecção
16.
J Atheroscler Thromb ; 24(9): 940-948, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28123148

RESUMO

AIM: Coronary collateral circulation (CCC) is crucial during an acute ischemic attack. Evidences showed that omentin-1 exhibited remarkable antiatherogenic effects and ischemia-induced revascularization. The aim of this study was to investigate the relationship between plasma omentin-1 levels and CCC in patients with ≥90% angiography-proven coronary occlusion. METHODS: 142 patients with ≥90% luminal diameter stenosis in at least one major epicardial coronary artery were recruited. Among them, 79 patients with Rentrop 0-1 grade were classified into the poor CCC group and 63 patients with Rentrop 2-3 grade were included into the good CCC group. The association between plasma omentin-1 levels and CCC status was assessed. RESULTS: Plasma omentin-1 level was significantly higher in patients with good CCC than those with poor CCC (566.57±26.90 vs. 492.38±19.70 ng/mL, p=0.024). Besides, omentin-1 was positively correlated with total cholesterol (TC), high-density lipoprotein, and gensini score but inversely with hyperlipidemia and body mass index (all p values<0.05). Multivariate regression analysis indicated that omentin-1 [odds ratio (OR)=1.002, 95% confidence interval (CI): 1.000-1.004, p=0.041)], TC, the number of the diseased vessels, a higher frequency of left circumflex artery and right coronary artery, chronic total occlusion, and gensini score remained as the independent predictors of good CCC. CONCLUSION: Higher plasma omentin-1 level was associated with better CCC development. Our findings suggest that omentin-1 may be an alternative marker for adequate CCC in patients with ≥90% coronary occlusion.


Assuntos
Circulação Colateral/fisiologia , Circulação Coronária/fisiologia , Estenose Coronária/sangue , Citocinas/sangue , Lectinas/sangue , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Colesterol/sangue , Angiografia Coronária , Oclusão Coronária/sangue , Oclusão Coronária/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Hiperlipidemias/sangue , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada
17.
Biochem Biophys Res Commun ; 434(3): 552-8, 2013 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-23583400

RESUMO

Previous studies have demonstrated an important interaction between angiotension II type 1 receptor (AT1R) and angiotension II (Ang II) -induced capillary formation from endothelial cells and vascular endothelial growth factor (VEGF). However, the underlying mechanism remains elusive. Recent studies revealed that the unfolded protein response regulates an angiogenic response by the kidney epithelium during ischemic stress. Therefore, in the present study, we investigated the effects of Ang II on AT1R-mediated capillary formation from endothelial cells and the possible involvement of the IRE1/JNK/p38 MAPK pathway. Our results show that Ang II (1 nmol/L) induced the expression of VEGF and enhanced capillary formation from endothelial cells in the Matrigel assay. This effect was significantly depressed by the AT1R blocker losartan and different inhibitors (irestatin, IRE1 specific inhibitor; SP600125, JNK specific inhibitor; SB203580, p38 MAPK specific inhibitor) but not by the AT2R blocker PD123319. Next, we investigated the effect of Ang II on the IRE1/JNK/p38 MAPK pathway and the 78kDA glucose regulated protein 78 (GRP78) activity in HUVECs and the role of the AT1 Receptor. The results show that Ang II activated both the IRE1/JNK/p38 MAPK pathway and GRP78 binding activity. These effects were markedly inhibited by the AT1R blocker losartan. The IRE1 specific inhibitor irestatin, the JNK specific inhibitor SP600125, and the p38 MAPK specific inhibitor SB203580 significantly inhibited Ang II-induced capillary formation from endothelial cells and VEGF expression but had no effect on GRP78. Collectively, these findings suggest for the first time that Ang II promotes capillary formation by inducing the expression of VEGF via Ang II type 1 receptor-mediated stimulation of the IRE1/JNK/p38 MAPK pathway.


Assuntos
Angiotensina II/farmacologia , Capilares/efeitos dos fármacos , Endorribonucleases/metabolismo , Endotélio Vascular/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Sequência de Bases , Células Cultivadas , Primers do DNA , Retículo Endoplasmático/metabolismo , Chaperona BiP do Retículo Endoplasmático , Endotélio Vascular/citologia , Humanos , Sistema de Sinalização das MAP Quinases , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Int J Cancer ; 108(2): 189-95, 2004 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-14639601

RESUMO

Suppression of alpha-mannosidases by chemicals has been shown to reduce the potentiality of growth and metastasis of various tumors. In our study, the effect of 6A8 alpha-mannosidase (MAN 6A8), recently discovered in our laboratory, on malignant behaviors of tumor cells was examined. Since the suppressive effect of chemicals on alpha-mannosidase is not specific, antisense technique was used to specifically inhibit expression of the MAN 6A8 in human nasopharyngeal carcinoma cells, CNE-2L2. Two cell clones, AS1 and AS2, with pronounced suppression of MAN 6A8 expression were developed. Wild-type (W), mock-transduced (M) and irrelevant DNA-transduced (IR) CNE-2L2 cells with normal expression of the enzyme were used as controls. Malignant behaviors of the cells were examined. Significant inhibition of growth of AS cells in vitro measured by MTT assay, colony formation and anchorage-independent colony formation was found. Pronounced inhibition of formation of tumors from AS cells inoculated into nude mice and metastasis was also observed. W, M and IR cells cultured in plate wells appeared dispersed with a fibroblastic or epithelial morphology, whereas AS cells were in compact sheets with an epithelioid organization. Since E-cadherin is the key factor in homophilic adhesion of epithelial cells, its expression on the surface of CNE-2L2 cells was determined. E-cadherin expression on AS cells was enhanced, whereas it was markedly diminished on W, M and IR cells. In addition, lamellipodia, which play an important role in cell spreading and mobility, almost disappeared on AS cells. The results demonstrate a significant suppressive effect of reduced expression of MAN 6A8 on malignant behaviors of CNE-2L2 cells.


Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , Neoplasias Nasofaríngeas/patologia , alfa-Manosidase/genética , Animais , Caderinas/metabolismo , Adesão Celular , Divisão Celular , Ensaio de Unidades Formadoras de Colônias , DNA Antissenso/genética , DNA Complementar/genética , Humanos , Camundongos , Camundongos Nus , Neoplasias Nasofaríngeas/enzimologia , Pseudópodes/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Células Tumorais Cultivadas , alfa-Manosidase/metabolismo
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